The 4-phenylbutyric acid sodium salt (sodium 4-phenylbutyrate) and its use for the treatment of a variety of illnesses, such as benign prostate hyperplasy, cancer, cystic fibrosis; HIV, kidney and liver failures, thalassemia and urea cycle disorders are known. For example, WO 85/04805 (Brusilow) discloses a process for waste nitrogen removal In human beings, wherein 4-phenylbutyrate is administered. DE 19,810,383 (Manhart, et. al.) describes 4-phenylbutyrate as apoptosis inducing agent for neoplastic therapy. WO 9937150 (Pandolfi et al.) describes a transcription therapy for cancers using a retinoic acid and/or an inhibitor of histone deacetylase. WO 93/07866, WO 9510271 or EP 725635 (Samid) disclose compositions and methods using phenylacetic acid derivatives for therapy and prevention of a number of pathologies, Including cancer, AIDS, anemia, and severe beta-chain hemoglobinopathies, which emerged in a number of U.S. patents. WO 9856370 (U.S. Pat. No. 6,207,195, Walsh et.) describes therapeutic sodium 4-phenylbutyrate containing nanospheres for treatment of cystic fibrosis by CFTR gene therapy. WO 9840078 (Rephaeli) discloses therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives with inhibitors of fatty acid beta-oxidation.
4-Phenylbutyric acid is rather quickly broken down in the human body by beta-oxidation to phenylacetic acid. This acid eliminates glutamine from cells, which is essential for the growth of cancer. A deficiency of glutamine in cancer cells results in apoptosis. In order to counteract the fast elimination of 4-phenylbutyrate from the body, about 10 to 40 g per patient and day are administered. In order to attain and maintain constant levels of the active ingredient in the plasma also infusion solutions are used. These, however, are unsuitable for ambulant treatment. The use of large amounts of 4-phenylbutyrate is also a commercial problem. The active compound is very expensive and has to be taken for several months up to years.
Accordingly, it would be desirable to have a 4-phenylbutyrate formulation that avoids the problems associated with application of large amounts of this compound. The formulation should be effective with lower amounts of the active ingredient. On repeated administration constant therapeutically effective plasma levels should be provided; exhibiting a minimum of fluctuations between the maximum and minimum concentrations of active Ingredient in the blood. A possible method of reducing the influx time of the active ingredient and of minimising fluctuations may be achieved by controlling the dissolution of the active ingredient over a longer period of time than is the case with conventional formulations. A solution to this problem is offered by the therapeutic system OROS® (F. Theeuwes, J. Pharm. Sci., Vol. 64, 12, 1987-1991, 1975). A disadvantage of the OROS systems is that they are technically difficult to produce.
A formulation would be desirable with a slow release rate providing low plasma level fluctuations, which remain constant over a relatively long period. Slow release formulations or retard formulations are known in the pharmaceutical art. However, they cannot simply be used for particular problems, but have to be individually designed for each active ingredient and for each indication. This requires some inventive ingenuity.
The release rate of the active ingredient from tablets or powders is influenced by the solubility characteristics of the active ingredient, which, in turn, depend upon solubility, particle size, specific surface area and interactions with other excipients. Dissolution may be retarded by means of diffusion barriers in the core of the tablet or in a film coating. Retarding dissolution by means of diffusion barriers in the core is a principle that is frequently used on account of its technical simplicity. It is possible to use various excipients, for example swelling agents, lipophilic substances or alternatively plastics, as diffusion barriers. The matrix, that is to say the homogeneous substance composition, can be such that the release of the active ingredient takes place by diffusion of the dissolved active ingredient, especially through the water-filled pores in the tablet core and if required in special cases by diffusion through the retarding substance which must for that purpose be in a suitable structural form. Alternatively the matrix also can be in a form that is subjected to slow erosion and in this way effects delayed release of the active ingredient.
In all those cases the diffusion path and the active diffusion surface for the release change with time. For that reason it is clear that with matrix systems neither in vivo nor in vitro is it usually possible to expect any release having linear kinetics, that is to say of the 0th order. Instead, the release is generally a function of the root of the time (Square root dissolution; Higuchi; J. Pharm. Sci. 52, 12, 1963, 1145). The validity of the Higuchi law for the hydrocolloid matrix has also been documented in numerous publications (Ford et al., Int. J. Pharm., 24, 1985, 327-338; 339-350; 1985).
Therapeutic dosage forms in which the medicinal substance is incorporated into a soluble or erodible matrix would be desirable on account of the ease of their manufacture, the low degree of variation between different manufacturing processes and because of the relatively low costs.
The use of hydrophilic gums, such as hydroxypropylmethyl-cellulose, as delaying matrix material is known and has been tested with a large number of active ingredients. No formulation has been disclosed hitherto that would be suitable for attaining the desired objectives with 4-phenylbutyrates.
The behaviour of a specific medicinal substance when combined with a retarding excipient cannot be calculated or generally predicted. Although the basic factors affecting release from matrix systems have been well researched, interactions between the retarding material on the one hand and the active ingredient and other excipients on the other can affect the retarding action in various ways.
The question of release kinetics is a multi-factored problem. Responsible factors are, in addition to the dissolution properties of the active ingredient, the rate of water absorption and thus the rate of swelling of the Interface to be penetrated, the diffusion co-efficient of the substance through the swollen mass and also the time-dependent thickness thereof. It can clearly be imagined that release of the 0th order is brought about by the existence of an equilibrium between the erosion of the tablet and the dissolution properties of the active ingredient, so that the diffusion paths for the substance remain constant during the dissolution time.
However, it is important to realise that it is impossible to predict, whether the release rate will be of the 0th or any other order. From the large number of known pharmaceutical excipients it is necessary to select those suitable for the desired purpose and to, process them in suitable quantity ratios, which must likewise be selected, to form an effective matrix system.